Enzyme Action Could Be Target for Diabetes, Heart Disease Treatments

Cardiac researchers at UC have found a new cellular pathway that could help in developing therapeutic treatments for obesity-related disorders, like diabetes and heart disease.

This research is being presented at the American Heart Association’s Scientific Sessions in Chicago Nov. 16.

Tapan Chatterjee, PhD, and researchers in the division of cardiovascular diseases found that action by the enzyme histone deacetylase 9 (HDAC9) can lead to obesity-induced body fat dysfunction and that HDAC9-regulated pathways could be targets for potential treatment options in obesity-related diseases.

Chatterjee says researchers in this study first identified HDAC9 regulator of fat cell differentiation within the living organism.

“Caloric intake promotes HDAC9 down-regulation to allow the conversion of precursor fat cells to “Ëœfunctional’ fat cells, capable of efficiently storing excess calories for future use and also maintaining whole body lipid and glucose stability,” he says. “Ideally, fat cells should function as a reversible storage site of excess calories and as an endocrine organ to maintain systemic lipid and glucose stability.

“Unfortunately, during chronic over-feeding, we find HDAC9 level is up-regulated in fat tissue, thereby blocking the conversion which leads to adipose tissue dysfunction and the onset of diseases such as diabetes, liver disease, high blood pressure and heart disease””the nation’s No. 1 killer.”

Researchers examined various members of the HDAC family of proteins and found that only HDAC9 showed a direct correlation to differentiation of precursor fat cells, both from human and mouse fat tissues.

“We believe that HDAC9 keeps precursor fat cells in the undifferentiated state; metabolic cues trigger HDAC9 down-regulation allowing conversion of the precursor cells to mature fat cells. We are exploring the cellular signaling mechanism that promotes such down-regulation of this enzyme during the normal fat cell differentiation process.”

Chatterjee says researchers were really interested in the tie between increased HDAC9 levels in fat tissue of mice and the caloric overload.

“Fat tissues from these obese mice showed dysfunction, with increased expression of pro-inflammatory agents and decreased expression of hormones responsible for maintaining whole body lipid and glucose stability,” he says. “The fat tissues of these mice are not capable of efficiently storing excess calories and are not able to perform proper endocrine functions.

“The adaptive response fails for some reason during chronic caloric overload, leading to the generation of fat tissue mass that is dysfunctional.”

Chatterjee says the HDAC9 level in fat cells is the underlying molecular culprit for dysfunctional fat tissue during obesity.

“Identification of HDAC9 as a novel regulator of fat cell differentiation and the finding that elevated HDAC9 levels are associated with adipose tissue dysfunction in obesity are extremely interesting and novel findings,” he continues.

Chatterjee’s team is pursuing studies to understand how diet regulates HDAC9 levels in fat tissue and how HDAC9 up-regulation can be prevented during diet-induced obesity through pharmacological means.

“Our findings may help lead researchers to targeted therapies that may prevent the development of obesity-related disorders in humans.”

This study was funded by a grant from the National Institutes of Health.